Primary biliary cirrhosis (PBC) is a chronic, progressive liver disease of unkown etiology. The disease is characterized by a disturbance in bile secretion and by inflammatory destruction of intrahepatic bile ducts. The process results in an increasing loss of interlobular bile ducts and eventually cirrhosis with portal hypertension. PBC is ultimately fatal; spontaneous permanent remissions have not been reported. Clinical, immunologic and histologic features, as well as excessive copper accumulation in the liver suggest that immune mechanisms and abnormal copper metabolism may be involved in the pathogenesis of this disease. A group of collaborating clinical investigators and basic scientist propose to continue and expand our prospective randomized controlled trial to evaluate the therapeutic efficacy of D-penicillamine in patients with PBC. We seek to understand the pathophysiologic mechanisms which contribute to the onset, progression and complication of this disease. We propose to evaluate the relationship of hepatic copper concentrations to progression, stability and remission of PBC. Results to date suggest that D-penicillamine may be beneficial, but the data is not yet conclusive. Little information is currently available regarding the metabolism of D-penicillamine in health or disease. In addition, D-penicillamine is not without significant side-effects and toxicity. The second and interrelated objective is, therefore, to study the metabolism and pharmacokinetics of D-penicillamine. We propose to develop tracer methods and radioimmunoassay techniques for D-penicillamine in a dog model which will allow direct measurement of the metabolic and pharmacokinetic studies of this drug in patients with PBC, healthy volunteers, and other disease controls in whom D-penicillamine has been recommended for therapy. Favorable patient referral to this Center affords a unique opportunity to expand the therapeutic trial and provide a data base that should allow this treatment trial to become a definitive study.